title: Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling.
abstract: Aspergillus fumigatus is the predominant airborne fungal pathogen in immunocompromised patients. Genetic defects in NADPH oxidase (chronic granulomatous disease [CGD]) and corticosteroid-induced immunosupression lead to impaired killing of A. fumigatus and unique susceptibility to invasive aspergillosis via incompletely characterized mechanisms. Recent studies link TLR activation with phagosome maturation via the engagement of autophagy proteins. In this study, we found that infection of human monocytes with A. fumigatus spores triggered selective recruitment of the autophagy protein LC3 II in phagosomes upon fungal cell wall swelling. This response was induced by surface exposure of immunostimulatory β-glucans and was mediated by activation of the Dectin-1 receptor. LC3 II recruitment in A. fumigatus phagosomes required spleen tyrosine kinase (Syk) kinase-dependent production of reactive oxygen species and was nearly absent in monocytes of patients with CGD. This pathway was important for control of intracellular fungal growth, as silencing of Atg5 resulted in impaired phagosome maturation and killing of A. fumigatus. In vivo and ex vivo administration of corticosteroids blocked LC3 II recruitment in A. fumigatus phagosomes via rapid inhibition of phosphorylation of Src and Syk kinases and downstream production of reactive oxygen species. Our studies link Dectin-1/Syk kinase signaling with autophagy-dependent maturation of A. fumigatus phagosomes and uncover a potential mechanism for development of invasive aspergillosis in the setting of CGD and corticosteroid-induced immunosupression.
authors.affiliation: Department of Medicine, University of Crete, 71300 Heraklion, Crete, Greece.
authors.forename: Irene
authors.initials: I
authors.lastname: Kyrmizi
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gresnigt
authors.forename: Tonia
authors.initials: T
authors.lastname: Akoumianaki
authors.forename: George
authors.initials: G
authors.lastname: Samonis
authors.forename: Prodromos
authors.initials: P
authors.lastname: Sidiropoulos
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Boumpas
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.forename: Georgios
authors.initials: G
authors.lastname: Chamilos
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism / Q000494:pharmacology; D000368:Aged; D001228:Aspergillosis / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology*; D001343:Autophagy / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D002478:Cells, Cultured; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000276:immunology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D000305:Adrenal Cortex Hormones; D000071187:Autophagy-Related Protein 5; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008869:Microtubule-Associated Proteins; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000072377:Syk Kinase; D019061:src-Family Kinases; C502778:ATG5 protein, human; C546929:CLEC7A protein, human; D000099181:Dectin-1; C477012:MAP1LC3A protein, human; C000606896:SYK protein, human